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NF‐κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation
Author(s) -
Williams Samuel A,
Chen LinFeng,
Kwon Hakju,
RuizJarabo Carmen M,
Verdin Eric,
Greene Warner C
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600900
Subject(s) - biology , trichostatin a , hiv long terminal repeat , rna polymerase ii , microbiology and biotechnology , gene knockdown , virus latency , chromatin , histone , transcription (linguistics) , psychological repression , polymerase , rna polymerase iii , histone deacetylase , virology , viral replication , long terminal repeat , rna , rna polymerase , virus , genetics , gene expression , cell culture , promoter , gene , linguistics , philosophy
Cells latently infected with HIV represent a currently insurmountable barrier to viral eradication in infected patients. Using the J‐Lat human T‐cell model of HIV latency, we have investigated the role of host factor binding to the κB enhancer elements of the HIV long terminal repeat (LTR) in the maintenance of viral latency. We show that NF‐κB p50–HDAC1 complexes constitutively bind the latent HIV LTR and induce histone deacetylation and repressive changes in chromatin structure of the HIV LTR, changes that impair recruitment of RNA polymerase II and transcriptional initiation. Knockdown of p50 expression with specific small hairpin RNAs reduces HDAC1 binding to the latent HIV LTR and induces RNA polymerase II recruitment. Similarly, inhibition of histone deacetylase (HDAC) activity with trichostatin A promotes binding of RNA polymerase II to the latent HIV LTR. This bound polymerase complex, however, remains non‐processive, generating only short viral transcripts. Synthesis of full‐length viral transcripts can be rescued under these conditions by expression of Tat. The combination of HDAC inhibitors and Tat merits consideration as a new strategy for purging latent HIV proviruses from their cellular reservoirs.